Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium
Cytochrome P450 (CYP) 1B1 is a heme-containing monooxygenase found mainly in extrahepatic tissues, including the retina. CYP1B1 substrates include exogenous aromatic hydrocarbons, such as dioxins, and endogenous bioactive compounds, including 17β-estradiol (E2) and arachidonic acid. The endogenous c...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2420 |
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| author | Yong-Seok Song Ismail S. Zaitoun Shoujian Wang Soesiawati R. Darjatmoko Christine M. Sorenson Nader Sheibani |
| author_facet | Yong-Seok Song Ismail S. Zaitoun Shoujian Wang Soesiawati R. Darjatmoko Christine M. Sorenson Nader Sheibani |
| author_sort | Yong-Seok Song |
| collection | DOAJ |
| description | Cytochrome P450 (CYP) 1B1 is a heme-containing monooxygenase found mainly in extrahepatic tissues, including the retina. CYP1B1 substrates include exogenous aromatic hydrocarbons, such as dioxins, and endogenous bioactive compounds, including 17β-estradiol (E2) and arachidonic acid. The endogenous compounds and their metabolites are mediators of various cellular and physiological processes, suggesting that CYP1B1 activity is likely important in maintaining proper cellular and tissue functions. We previously demonstrated that lack of CYP1B1 expression and activity are associated with increased levels of reactive oxygen species and oxidative stress in the retinal vasculature and vascular cells, including retinal endothelial cells (ECs). However, the detailed mechanism(s) of how CYP1B1 activity modulates redox homeostasis remained unknown. We hypothesized that CYP1B1 metabolism of E2 affects bone morphogenic protein 6 (BMP6)-hepcidin-mediated iron homeostasis and lipid peroxidation impacting cellular redox state. Here, we demonstrate retinal EC prepared from <i>Cyp1b1</i>-deficient (<i>Cyp1b1<sup>−/−</sup></i>) mice exhibits increased estrogen receptor-α (ERα) activity and expresses higher levels of BMP6. BMP6 is an inducer of the iron-regulatory hormone hepcidin in the endothelium. Increased hepcidin expression in <i>Cyp1b1<sup>−/−</sup></i> retinal EC resulted in decreased levels of the iron exporter protein ferroportin and, as a result, increased intracellular iron accumulation. Removal of excess iron or antagonism of ERα in <i>Cyp1b1<sup>−/−</sup></i> retinal EC was sufficient to mitigate increased lipid peroxidation and reduce oxidative stress. Suppression of lipid peroxidation and antagonism of ERα also restored ischemia-mediated retinal neovascularization in <i>Cyp1b1<sup>−/−</sup></i> mice. Thus, CYP1B1 expression in retinal EC is important in the regulation of intracellular iron levels, with a significant impact on ocular redox homeostasis and oxidative stress through modulation of the ERα/BMP6/hepcidin axis. |
| first_indexed | 2024-03-11T09:42:13Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:42:13Z |
| publishDate | 2023-01-01 |
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| spelling | doaj.art-ca1438f2c7194925a6ea627d6be308a62023-11-16T16:56:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243242010.3390/ijms24032420Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal EndotheliumYong-Seok Song0Ismail S. Zaitoun1Shoujian Wang2Soesiawati R. Darjatmoko3Christine M. Sorenson4Nader Sheibani5Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartment of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartment of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartment of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USAMcPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USADepartment of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USACytochrome P450 (CYP) 1B1 is a heme-containing monooxygenase found mainly in extrahepatic tissues, including the retina. CYP1B1 substrates include exogenous aromatic hydrocarbons, such as dioxins, and endogenous bioactive compounds, including 17β-estradiol (E2) and arachidonic acid. The endogenous compounds and their metabolites are mediators of various cellular and physiological processes, suggesting that CYP1B1 activity is likely important in maintaining proper cellular and tissue functions. We previously demonstrated that lack of CYP1B1 expression and activity are associated with increased levels of reactive oxygen species and oxidative stress in the retinal vasculature and vascular cells, including retinal endothelial cells (ECs). However, the detailed mechanism(s) of how CYP1B1 activity modulates redox homeostasis remained unknown. We hypothesized that CYP1B1 metabolism of E2 affects bone morphogenic protein 6 (BMP6)-hepcidin-mediated iron homeostasis and lipid peroxidation impacting cellular redox state. Here, we demonstrate retinal EC prepared from <i>Cyp1b1</i>-deficient (<i>Cyp1b1<sup>−/−</sup></i>) mice exhibits increased estrogen receptor-α (ERα) activity and expresses higher levels of BMP6. BMP6 is an inducer of the iron-regulatory hormone hepcidin in the endothelium. Increased hepcidin expression in <i>Cyp1b1<sup>−/−</sup></i> retinal EC resulted in decreased levels of the iron exporter protein ferroportin and, as a result, increased intracellular iron accumulation. Removal of excess iron or antagonism of ERα in <i>Cyp1b1<sup>−/−</sup></i> retinal EC was sufficient to mitigate increased lipid peroxidation and reduce oxidative stress. Suppression of lipid peroxidation and antagonism of ERα also restored ischemia-mediated retinal neovascularization in <i>Cyp1b1<sup>−/−</sup></i> mice. Thus, CYP1B1 expression in retinal EC is important in the regulation of intracellular iron levels, with a significant impact on ocular redox homeostasis and oxidative stress through modulation of the ERα/BMP6/hepcidin axis.https://www.mdpi.com/1422-0067/24/3/2420retinal vasculatureiron homeostasisBMP6hepcidinferroportineNOS |
| spellingShingle | Yong-Seok Song Ismail S. Zaitoun Shoujian Wang Soesiawati R. Darjatmoko Christine M. Sorenson Nader Sheibani Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium International Journal of Molecular Sciences retinal vasculature iron homeostasis BMP6 hepcidin ferroportin eNOS |
| title | Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium |
| title_full | Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium |
| title_fullStr | Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium |
| title_full_unstemmed | Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium |
| title_short | Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium |
| title_sort | cytochrome p450 1b1 expression regulates intracellular iron levels and oxidative stress in the retinal endothelium |
| topic | retinal vasculature iron homeostasis BMP6 hepcidin ferroportin eNOS |
| url | https://www.mdpi.com/1422-0067/24/3/2420 |
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